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High dose oral lansoprazole versus intravenous esomeprazole in preventing re-bleeding for patients with peptic ulcer bleeding
after successful endoscopic therapy, a prospective, randomized trial
2Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, No. 252, Wuxing St., Taipei 11031, Taiwan
Corresponding Author: Hwai-Jeng Lin, M.D., FACGDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, No. 252, Wuxing St., Taipei 11031, Taiwan
Word counts: 2381
Study highlights:
What is current knowledge?
1. High dose intravenous PPI is currently suggested as adjuvant therapy for high-risk bleeding peptic ulcers after successful endoscopic therapy.
2. High dose oral PPI can achieve similar intragastric pH compared with high dose intravenous PPI.
3. Whether high dose oral PPI can achieve similar clinical efficacy compared with high dose intravenous PPI as adjuvant therapy for high-risk bleeding peptic ulcer is unknown so far.
What is New Here?1. High dose oral PPI can achieve similar clinical efficacy compared with high
dose intravenous PPI as adjuvant therapy for high-risk bleeding peptic ulcer in terms of re-bleeding rate, blood transfusion, surgery and mortality.
2. Patients receiving high dose oral PPI as an adjuvant therapy have a shorter hospital stay compared with those receiving high dose intravenous PPI.
Abstract
Objectives The use of high dose proton pump inhibitor (PPI) after endoscopic therapy
for peptic ulcer bleeding has been recommended as adjuvant therapy. Whether oral PPI can replace intravenous PPI in the prevention of re-bleeding in these patients is unknown. Our aim was to compare the clinical efficacy of oral and intravenous PPIs after successful endoscopic therapy for patients with bleeding peptic ulcers. Methods
This is a prospective, randomized, comparative study. Patients with high-risk bleeding peptic ulcers (Forrest Ia, Ib, or IIa) after successful endoscopic therapy (heater probe or hemoclip placement) were enrolled in this study. They were randomly assigned as oral lansoprazole (30mg four times daily) or intravenous esomeprazole group (40mg intravenous infusion every 6 hours) for 3 days followed by oral lansoprazole 30mg and esomeprazole 40mg per day respectively. Primary outcome of the study was re-bleeding rate within 14 days. Secondary outcome included hospital stay, volume of blood transfusion, surgical intervention and mortality rate within 1 month.Results
From April 2011 to Feb 2012, 100 patients (50 patients in the oral group and 50 patients in the intravenous group) were enrolled in this study. The re-bleeding rates were 4% (2/50) in the intravenous group and 4% (2/50) in the oral group (p=1). There was no difference between the two groups with regards to the hospital stay, volume of blood transfusion, surgery or mortality rate. The mean duration of hospital stay was 1.8 days in the oral group and 3.9 days in the intravenous group (p<0.01).Conclusion
The results of the study suggest that oral and intravenous PPIs are equally effective to prevent re-bleeding for patients with high-risk bleeding peptic ulcers after successful endoscopic therapy. Patients receiving oral PPIs have a shorter hospital stay.
Introduction
A bleeding peptic ulcer remains a serious medical problem with
significant morbidity and mortality. Endoscopic therapy significantly
reduces further bleeding, surgery, and mortality in patients with bleeding
peptic ulcers (1) and is now recommended as the first hemostatic modality
for these patients (1, 2).Following endoscopic therapy, proton pump inhibitor (PPI) can reduce re-
bleeding and surgery (3, 4). The therapeutic efficacy of PPI is related to its
potent inhibition of gastric acid (5), because acid and acid dependent
protease activity impair blood clotting (6, 7). However, the optimal route,
dose and duration of PPI therapy after endoscopic therapy remain
controversial. Oral PPI has been found to be effective in preventing re-bleeding in
previous studies (8-13). For cost effectiveness, it is worth evaluating the
benefits of oral PPI and intravenous (IV) PPI in patients with peptic ulcer
bleeding (14). Recently, Laine et al (15) and Javid et al (16) proved that
oral PPI can achieve a similar intragastric pH with that receiving IV PPI.
Following up on these evidences, we have observed a similar preventing
capability of oral PPI clinically (17).Therefore, oral PPI may be able to
replace IV PPI after successful endoscopic therapy. In this study, we attempted to evaluate two different routes, using high
dose PPIs to prevent re-bleeding for bleeding peptic ulcer patients after
successful endoscopic therapy.
METHODS
Design and Patients
From April 2011 to Feb 2012, peptic ulcer patients with high-risk stigmata
were considered eligible if they fulfilled the following inclusion criteria: (i)
underwent urgent endoscopy within 24 h after presentation, (ii) had peptic
ulcers in the stomach or duodenum, (iii) had high-risk stigmata including
active bleeding (Forrest IA, IB), or non-bleeding visible vessels (NBVV,
Forrest IIA) and (iv) successful hemostasis was achieved with endoscopic
heat probe thermocoagulation or hemoclip placement. Written informed
consent was obtained from each patient before enrolment. Patients were excluded from the study if they were pregnant, did not
obtain initial hemostasis with endoscopic therapy, did not give written
informed consent, had bleeding tendency (platelet count <50X109 l-1, serum
prothrombin <30% of normal, or were taking anticoagulants), had used PPI
within 14 days of enrolment, had uremia or bleeding gastric cancer.
Endoscopic procedure
The methods utilized with regards to heater probe thermocoagulation and hemoclip placement were in our previous publications (5, 18). Active bleeding was defined as a continuous blood spurting (Forrest IA) or oozing (Forrest IB) from the ulcer base. An NBVV at endoscopy was defined as a discrete protuberance at the ulcer base (Forrest IIA). All patients underwent endoscopic biopsy at gastric antrum for rapid urease test (CLO test). Those who were positive for urease test received a 1-week course of esomeprazole (40 mg twice daily, Nexium®;AstraZeneca, Molndal, Sweden) or lansoprazole (30 mg twice daily, takepron OD, Takeda Ltd, Japan), plus clarithromycin (500
mg twice daily) and amoxicillin (1 g twice daily) after discharge.
Randomization process
Enrolled patients were randomly allocated into two groups using sealed
envelopes containing a therapeutic option (either IV esomeprazole or oral
lansoprazole) derived from a random number table. In the esomeprazole
(ESO) group, 40 mg continuous infusion of ESO was administered every 6 h
for 3 days. Thereafter, the patients received oral ESO 40 mg once daily for 2
months. In the lansoprazole (LAN) group, we gave oral LAN 30 mg four times
daily for 3 days followed by once daily for 2 months. All of the patients were
admitted after endoscopic therapy and were discharged and followed in the
outpatient department. In the LAN group, patients were allowed at home if
absence of shock and initial hemoglobin greater than 10 g/L. For them, one
research assistant would contact with patients daily and check vital signs and
stool color.
Assessments
Patients’ vital signs were checked every hour for the first 12 h, every 2 h
for the second 12 h, every 4 h for the following 24 h until they became
stable, and then four times daily during admission. The hemoglobin level and
hematocrit were checked at least once daily, and blood transfusion was given
if the hemoglobin level decreased to lower than 90 g/L or if the patient’s vital
signs deteriorated. Shock was defined as systolic blood pressure <100 mmHg
and a pulse rate of >100 /min accompanied by cold sweats, pallor or
oligurea. Initial endoscopic hemostasis was defined as no visible hemorrhage
with observation for 3 min. Ultimate hemostasis was defined as no re-
bleeding within 14 days after endoscopic therapy. Re-bleeding was suspected
if unstable vital signs, continuous tarry, bloody stool or a drop of hemoglobin
level >20 g/L within 24 h were noted. For these patients, an emergent
endoscopy was performed immediately. Re-bleeding was concluded if active
bleeding, fresh blood or blood clots were found. All patients with re-bleeding
were treated with rescue endoscopic therapies including heater probe
thermocoagulation or hemoclip placement.At entry to the study, the following data were recorded: age, sex, location
of the ulcer (esophagus, stomach, duodenum or stoma), ulcer size,
appearance of the gastric contents (clear, coffee ground, or blood), bleeding
stigmata (spurting, oozing or NBVV), volume of blood transfusion at entry,
presence of shock, hemoglobin, nonsteroidal anti-inflammatory drug
ingestion, cigarette smoking, alcohol drinking, Rockall score and comorbid
illness. The Rockall scoring system was used to assess the severity of
bleeding in both groups (19).
End-points
The primary end-point was 14-day re-bleeding rate. Volume of blood
transfusion, surgery, mortality within 30 days, and hospital stay were
considered as secondary end-points.
Statistics
The sample size estimation was based on an expected re-bleeding rate of
30% in the LAN group. The trial was designed to detect a 25% difference in
favor of the ESO group with a type I error of 0.05 and type II error of 0.05. At
least 65 patients were essential for each group. Taking into account a
possible drop-out rate of 15%, 78 patients were enrolled for each group in
this study. We used unpaired Student’s t-test to compare the numerical
variables including age, ulcer size, volume of blood transfused, hemoglobin,
and length of hospital stay between the two groups. Pearson’s c2 test and
Fisher’s exact test were used (if expected frequency in any of the cells was
<10) to compare categorical variables such as the location of the bleeders,
endoscopic findings, gastric contents, number of patients with Helicobacter
pylori infection, shock, comorbid illness, hemostasis, emergent surgery, and
mortality between the two groups. SPSS version 17.0 was used for analysis.
All statistic examinations were two-tailed and a probability value of <0.05
was considered significant.
ResultsFrom January 2011 to Feb 2012, 126 patients were found to have the
high-risk stigmata of active bleeding, or NBVV at Changhua Christian
Hospital. Twenty six patients were excluded from the study for the
following reasons: lack of informed consent (n = 3), bleeding tendency (n
= 8), gastric malignancy (n = 5), and prior use of PPI (n = 10) (Figure 1).
Finally, 100 patients were enrolled in this study (50 in the ESO group and
50 in the LAN group). Four patients in this study (n=2 for each group)
received hemoclip placement and others received heater probe
thermocoagulation. The two groups were well matched for the factors
affecting outcome (Table 1). Table 2 shows the clinical outcomes of this study. In the LAN group, 25
patients were allowed to stay at home due to absence of shock and initial
hemoglobin greater than 10 g/L. Re-bleeding occurred in 2 (4%) patients
in the ESO group and 2 patients (4%) in the LAN group within 14 days (p =
1). All re-bleeding episodes occurred on the second day of enrolment. All
these four patients received a second heater probe thermocoagulation and
obtained ultimate hemostasis. The mean duration of hospital stay was 3.9
days in the ESO group and 1.8 days in the LAN group (p<0.01). There was
no patient with mortality or surgical intervention in both groups. The
volumes of blood transfusion were comparable between both groups
(mean, ESO: 781 ml, LAN: 520 ml, p>0.1)
DISCUSSION
The most important finding of current study is to show that both oral and
IV PPIs are equally effective to prevent re-bleeding after endoscopic
therapy for high-risk bleeding peptic ulcers. In addition, we found that oral
route PPIs can further decrease hospital stay and therefore decrease
medical expenses associated with peptic ulcer bleeding in this trial. This is,
to our knowledge, the first randomized controlled trial to compare the
clinical outcome (including re-bleeding rate, blood transfusion, surgery,
hospital and mortality rate) of high dose oral and IV PPIs following
endoscopic therapy for patients with bleeding peptic ulcer. The use of PPIs following endoscopic therapy for bleeding peptic ulcers
can help to stabilize blood clots, promote platelet aggregation and prevent
fibrinolysis (6,7). In our previous study and recent meta-analysis , PPIs
have been found to be superior to H2 blockers or placebo in preventing re-
bleeding following endoscopic therapy for peptic ulcers (20, 21). Current
guidelines suggest a high dose PPI followed by continues infusion as
standard adjuvant pharmacotherapy for bleeding peptic ulcers especially
in the Western countries (22, 23). This recommendation was based on
previous studies that show that high doses of PPI followed by continuous
infusion are able to sustain a higher intragastric pH (24, 25). Although high doses intravenous PPI are demonstrated to be superior to
placebo(26) , there is no evidence showing high doses of intravenous PPIs are
superior to oral PPIs with regards to the clinical outcome of bleeding peptic
ulcer patients following endoscopic therapy. As compared with the
intravenous route administration of PPI, oral PPI is more attractive because of
its availability and cost-effectiveness. In our recent study, we found that both
oral and intravenous administration of regular doses of PPIs have a similar re-
bleeding rate (16.7% vs. 15.4% for IV omeprazole vs. oral rabeprazole)
following endoscopic therapy for bleeding peptic ulcers (17). Banerjee et al
found that oral buffered esomeprazole (40mg po) is superior to IV
pantoprazole (40mg IV every 12h) to achieve intragastric pH > 6 in healthy
volunteers (27) . Laine et al conducted the first study to compare the acid
suppression effect of oral and intravenous lansoprazole in bleeding peptic
ulcer patients (15). They randomized patients into two groups: (a)
intravenous lansoprazole (90mg bolus followed by 9mg/h) and (b)
intermittent high dose oral lansoprazole (120mg bolus followed by 30mg
every three hours). Patients were monitored with a 24-hour pH monitor. They
found that a mean pH above 6 was achieved 1 hour earlier ( 2-3 hours vs. 3-4
hours) in the intravenous compared with oral group. They concluded that
frequent oral PPI can replace currently recommended intravenous PPI. Javid
et al from India found there is no difference among different PPIs and
different routes of these PPIs (omeprazole, pantoprazole and rabeprazole ) in
intragastric pH above 6 for 72 hours after endoscopic therapy for bleeding
peptic ulcers (16). A pilot study from Bajaj et al suggests oral pantoprazole is
similar to IV pantoprazole on 30-day re-bleeding rate (28). Based on these
studies, we conducted this study to clarify the clinical efficacy of high dose
oral and intravenous PPIs after successful endoscopic therapy for patients
with bleeding peptic ulcers.In this randomized comparative trial, we found patients with oral and
intravenous PPI have a similar clinical outcome, including recurrent
bleeding, blood transfusion, surgery and mortality. Interestingly, we found
that patients in the oral PPI group have a shorter hospital stay compared
with the IV group (1.8 days vs. 3.9 days). This is the first study to prove
the finding of similar intragastric pH via different routes of administration
is also valid for the clinical outcomes (15, 16). The low rebleeding rate of
4% in both groups is lower than our previous study of regular dose PPIs
but is comparable to a multicenter study with high dose intravenous
esomeprazole (17,26). This suggests that high doses rather than regular
doses of PPI via the oral route can achieve comparable clinical outcomes
with high dose intravenous PPI. This is important in two ways. First, the cost associated with the
pharmacotherapy can be reduced. The cost of oral PPI is one tenth the
cost of the intravenous PPI in Taiwan. In addition, a patient with oral PPI
can be discharged earlier in our study. Taking both together, approaches
with high dose oral PPI can be more economical than high dose
intravenous PPI. Second, the oral route administration of PPI is easy and
dose not require frequent monitoring for the infusion site reactions (such
as edema, thrombophlebitis, and so on). In addition, the use of oral
disintegrating lansoprazole can be taken without water and repeated
endoscopy can be performed without waiting for gastric emptying (29). When total enrolled number of patients reached 100, we analyzed the
results. We found that both groups had the same re-bleeding rate (4%),
therefore, we terminated the trial. There were some limitations with
regards to this study that are worth noting. First, not all patients were
admitted for re-bleeding observation. For reasons related to cost
effectiveness, we allowed patients without shock and high initial
hemoglobin (>10g/L) to stay at home in the LAN group (n=25). They were
well educated about the signs of re-bleeding and recorded vital signs at
least four times daily. A research assistant would contact them daily.
Second, we applied two different therapeutic modalities (heater probe
thermocoagulation and hemoclip placement) in this study. However, only
a few patients received hemoclip placement (two patients in each group).
The four re-bleeders were those receiving heater probe
thermocoagulation. Therefore, this factor affected the result minimally.
Third, the study population is a Chinese cohort with an H. pylori infection
rate of 68%. We did not test for the CYP2C19 genotype status of our
patients. Thus, our patients may have a similar good response to high
dose IV and oral PPI for intragastric pH control and may have resulted in a
similar clinical outcome.
Conclusion
We conclude that oral and intravenous large dose PPIs are equally
effective as adjuvant therapy to prevent re-bleeding for patients with
high-risk bleeding peptic ulcers after successful endoscopic therapy.
Oral PPIs have the advantage of shortening hospital stay.
Table1. Clinical variables of patients at entry to the study
ESO (n=50) LAN (n=50)
Age (yr, s.e.m.)* 65.0 (2.2) 62.7 (2.3)Sex (%) Male 37 (74%) 34 (68%) Female 13 (26%) 16 (32%)Locations of ulcer (%) Stomach 22 (44%) 18 (32%) Duodenum 28 (56%) 32 (68%) Endoscopic findings (%)
Spurting 6(12%) 4 (8%)Oozing 15 (30%) 18 (36%)NBVV 29 (58%) 28 (56%)
Gastric contents (%)Blood 14 (28%) 9 (18%)Coffee grounds 22 (44%) 20 (40%)Clear 14 (28%) 21 (42%)
Shock (%) 21 (42%) 18 (36%)Medical comorbidity (%) 33 (66%) 30 (60%)Ulcer size (cm, s.e.m.) 1.4 (0.2) 1.6 (0.2)H. pylori infection (%) 26 (68.4%) 25 (68.6%)Hemoglobin (g/l, s.e.m.) 9.6(0.34) 10.7(0.38)Rockall score (mean, s.e.m.) 5.3 (0.2) 5.3 (0.3)
Note: *Numerical variables expressed as mean and standard error of mean (s.e.m.).
There were no statistically significant differences between the two groups
Table2. Clinical outcomes of patients according to routes of PPI
ESO (n=50) LAN (n=50)
Recurrent bleeding (%)# 2 (4%) 2 (4%)
Hospital stay (days, s.e.m.)#* 3.9 (0.2) 1.8(0.3)
Volume of blood transfusion (ml, s.e.m.) 781 (145) 520 (101)
Surgery (%) 0 (0%) 0 (0%)
Death (%) 0 (0%) 0 (0%)
NOTE: #Numerical variables expressed as mean with standard error of mean (s.e.m.).
*Hospital stay: p<0.001 between both groups, others: p>0.1
Figure 1. Flow chart illustrating the study progress from initial enrollment, through
randomization, to primary endpoint assessment.
Patients with active bleeding, non-bleeding visible vessel, or clots(n=126)
Patients randomized and treated(n=100)
Nexium Lansoprazole(n=50) (n=50)
Re-bleeding Hemostasis(n=2) (n=48)
Re-bleeding Hemostasis(n=2) (n=48)
Exclusion (n=26)Lack of consent (n=3)Bleeding tendency (n=8)Gastric malignancy (n=5)Prior PPI usage (n=10)
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